SUMMARY/ABSTRACT Gastric cancer is the third leading cause of cancer-associated death worldwide. The 2015 global cancer statistics report indicated an estimated 951,600 new gastric cancer cases and 723,100 deaths occurred in 2012. Several studies have reported frequent association of gastric adenocarcinoma with Helicobacter pylori (H. pylori) infection. The World Health Organization has classified H. pylori as a class I carcinogen and the main risk factor for gastric cancer. Despite efforts to eradicate H. pylori, infection remains a global health problem with almost half of the world's population infected. Of note, chronic infection with H. pylori persists for several decades before the development of gastric cancer. This latency in the development of gastric cancer and the fact that only 1% of infected individuals develop cancer suggests that epithelial cells have an inherent protective capacity against cellular transformation by H. pylori. When epithelial cells lose their protective capacity, they become prone to the carcinogenic effects of H. pylori, leading to the development of intestinal metaplasia, gastric dysplasia and progression to cancer. We and others have reported that trefoil factor 1 (TFF1) expression is lost in nearly all human gastric cancers. Our studies have shown that TFF1 is a potent tumor suppressor and anti-inflammatory protein. Our preliminary data in this proposal, using in vitro and in vivo models as well as carcinogenic H. pylori strains, demonstrate that TFF1 suppresses activation of STAT3 and expression of its target genes that are involved in proliferation, anti-apoptosis angiogenesis, invasion, and immune evasion. Based on our novel findings, we hypothesize that TFF1 is as a gatekeeper protein in gastric epithelial cells that suppresses the dynamic pro-inflammatory oncogenic cross-talk between STAT3 and NFkB in gastric tumorigenesis. Our goal is to understand the molecular and functional consequences of loss of TFF1 as they relate to STAT3 and NF??B cross-talk in H. pylori-induced molecular signaling in the multi- step gastric carcinogenesis cascade. In this proposal, we will investigate the mechanisms by which TFF1 regulates STAT3 in gastric tumorigenesis (Aim 1). We will determine the molecular and biological functions of TFF1 loss and activation of STAT3- NFkB pro-inflammatory cross-talk signaling in gastric tumorigenesis in Aim 2. In addition, we will investigate the clinical significance and associations between TFF1 loss and activation of NFkB and STAT3 across stages of human gastric tumorigenesis (Aim 3). We will also test the therapeutic significance of inhibiting STAT3 as a single agent or in combined regimens in pre-clinical models of gastric tumorigenesis. This proposal tackles etiology-based biologically-relevant questions to uncover novel information regarding the role of TFF1-loss in shaping the H. pylori-induced inflammation and carcinogenic signaling in the multi-step gastric tumorigenesis. A successful completion of this project will have a positive impact on understanding the biology and identification of diagnostic, prognostic and possibly therapeutic targets in gastric cancer.